Cited by 544Estrogen and related hormone effectsGenomics and Chromatin DynamicsStress Responses and Cortisol

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Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation

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Reddy, Timothy E., Pauli, Florencia, Sprouse, Rebekka O., Neff, Norma F., Newberry, Kimberly M., Garabedian, Michael J., Myers, Richard M.·2009·Genome Research

DOI 10.1101/gr.097022.109PMC PMC2792167

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Abstract

The glucocorticoid steroid hormone cortisol is released by the adrenal glands in response to stress and serves as a messenger in circadian rhythms. Transcriptional responses to this hormonal signal are mediated by the glucocorticoid receptor (GR). We determined GR binding throughout the human genome by using chromatin immunoprecipitation followed by next-generation DNA sequencing, and measured related changes in gene expression with mRNA sequencing in response to the glucocorticoid dexamethasone (DEX). We identified 4392 genomic positions occupied by the GR and 234 genes with significant changes in expression in response to DEX. This genomic census revealed striking differences between gene activation and repression by the GR. While genes activated with DEX treatment have GR bound within a median distance of 11 kb from the transcriptional start site (TSS), the nearest GR binding for genes repressed with DEX treatment is a median of 146 kb from the TSS, suggesting that DEX-mediated repression occurs independently of promoter-proximal GR binding. In addition to the dramatic differences in proximity of GR binding, we found differences in the kinetics of gene expression response for induced and repressed genes, with repression occurring substantially after induction. We also found that the GR can respond to different levels of corticosteroids in a gene-specific manner. For example, low doses of DEX selectively induced PER1 , a transcription factor involved in regulating circadian rhythms. Overall, the genome-wide determination and analysis of GR:DNA binding and transcriptional response to hormone reveals new insights into the complexities of gene regulatory activities managed by GR.

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Authors: Reddy, T. E., Pauli, F., Sprouse, R. O., Neff, N. F., Newberry, K. M., Garabedian, M. J., & Myers, R. M.
Affiliations: HudsonAlpha Institute for Biotechnology (US)
Stanford Medicine (US)
New York University (US)
ORCID: Reddy, Timothy E.
Pauli, Florencia
Neff, Norma F.
Newberry, Kimberly M.
Garabedian, Michael J.
Myers, Richard M.
Venue: Genome Research
Publisher: Cold Spring Harbor Laboratory
Published: 2009-10-02
Volume: 19
Issue: 12
Pages: 2163-2171
ISSN: 1088-9051 (ISSN-L)
DOI: 10.1101/gr.097022.109
PMC: PMC2792167
OpenAlex: W2113112889
Cited by: 543
References: 44
Citations by year: 2026: 16 · 2025: 15 · 2024: 32 · 2023: 35 · 2022: 25 · 2021: 28 · 2020: 29 · 2019: 35 · 2018: 34 · 2017: 47 · 2016: 49 · 2015: 41 · 2014: 32 · 2013: 35 · 2012: 38
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genome Research (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Philip Morris International
National Institutes of Health
National Human Genome Research Institute (U54HG004576)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: glucocorticoid receptor, dexamethasone, cortisol, transcriptional repression, transcriptional activation, Per1, circadian rhythm, hormone dose-response, gene expression regulation
MeSH terms: Binding Sites, Dexamethasone, Gene Expression Regulation, Humans, Lung, Proteins, Receptors, Glucocorticoid, RNA, Messenger, Genome, Sequence Analysis, DNA, Chromatin Immunoprecipitation

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Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation

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